ABSTRACT Diabetes Mellitus is a serious chronic disease in which the physiological homeostatic controls in the body becomes less responsive to changing blood glucose levels. In Type II diabetes the body makes little or no insulin (the hormone responsible for reducing blood glucose levels) or the mechanisms down stream of insulin become unresponsive to the insulin produced. Type II diabetes is the most prevalent form of the disease accounting for over 90% of the >20 million people in the US with the disease. Diabetic peripheral neuropathy is one of the primary complications of diabetes, and up to 50% of diabetic patients will present with this issue. This leads to problems with cutaneous wound healing and to ulcerations and advanced infections particularly in the foot. Diabetic Foot Infections (DFI) and associated diabetic foot osteomyelitis (DFO) are serious infections which can lead to very high levels of sequelae including amputation. The DFO infections are complex and difficult to treat bone infections often requiring long-term antibiotic treatment and surgery.! Here we lay out a potential therapeutic solution to this problem based on the use of bisphosphonate (BP)-antimicrobial conjugates that will target to bone and release their antimicrobial payload at the bone surface. Our strategy will directly target the bacterial biofilm reservoir on the bone and lower the amount of systemic drug treatment needed, limiting extra-osseous exposure. Our preliminary results support testing the feasibility of using this highly innovative strategy for the treatment of DFO. To support establishing the feasibility of this approach we set out three specific aims: 1) we will synthesize novel drug candidates based on an advanced newer generation fluoroquinolone, moxifloxacin (MOXI), including several linkage strategies to tune the bone target and release kinetics, 2) we will test these BP-MOXI conjugates in vitro using hydroxyapatite bone mineral models of biofilm infections, and 3) we will test the conjugate with the most favorable release kinetics and bactericidal activity (from aim two) in a type II diabetic mouse model of osteomyelitis. There is a great unmet medical need for novel and effective treatments for DFO, and we believe that our novel and innovative BP-MOXI conjugate, that is capable of releasing MOXI directly into the site of bone infection, will provide a transformative treatment for this disease. Here we lay out the strategy to prove the feasibility of this approach. !